Cytochrome P450 3A4 and P‐glycoprotein Expression in Human Small Intestinal Enterocytes and Hepatocytes: A Comparative Analysis in Paired Tissue Specimens

Richter, Oliver von; Burk, Oliver; Fromm, Martin F.; Thon, K.; Eichelbaum, Michel; Kivistö, Kari T.

doi:10.1016/j.clpt.2003.10.008

Cited by 245 publications

(208 citation statements)

References 47 publications

Supporting

Mentioning

183

Contrasting

Unclassified

Order By: Relevance

“…29 CYP3A5*1 carrier state is associated with higher hepatic and intestinal CYP3A5 expression and activity, [30][31][32][33] thus in CYP3A5 expressers, more diltiazme N-demethylation metabolites are formed resulting in stronger inhibition of CYP3A activity, which might explain the finding of our study. In addition, in recent years, expression of CYP3A enzyme has been shown to be transcriptionally regulated by nuclear receptor pregnane X receptor (PXR).…”

Section: Cyp3a5*3 and Diltiazem-tacrolimus Interactionsupporting

confidence: 77%

Effects of diltiazem on pharmacokinetics of tacrolimus in relation to CYP3A5 genotype status in renal recipients: from retrospective to prospective

et al. 2010

Pharmacogenomics J

View full text Add to dashboard Cite

The impact of CYP3A5*3, a CYP3A5 nonexpresser genotype, on inhibitory effects of diltiazem on tacrolimus metabolism has not been assessed. In retrospective study, when coadministered with diltiazem, mean increments in dose-adjusted C 0D7 , C max and AUC 0-12 h for tacrolimus were larger in CYP3A5 expressers than in CYP3A5 nonexpressers (48.7 vs 3.7%, 31.7 vs 17.2% and 38.2 vs 18.5%, respectively). Subsequently, a prospective study was carried out, patients were randomized to algorithm-predicted dosing or standard dosing. For CYP3A5 expressers, an algorithm guided by CYP3A5 and diltiazem significantly reduced tacrolimus maintenance dosage (P ¼ 0.009) and improved the accuracy of tacrolimus initial dose, resulting in reduction in out-of-range C 0 after initial dose (P ¼ 0.002) and dose adjustments (P ¼ 0.004). However, for CYP3A5 nonexpressers, primary end points were not achieved, and tacrolimus-sparing effect of diltiazem was not remarkable. Our study results show that CYP3A5 genotype-guided tacrolimus-diltiazem combination is a promising therapy in renal transplant recipients in the early postoperative stage.

show abstract

Section: Cyp3a5*3 and Diltiazem-tacrolimus Interactionsupporting

confidence: 77%

Effects of diltiazem on pharmacokinetics of tacrolimus in relation to CYP3A5 genotype status in renal recipients: from retrospective to prospective

et al. 2010

Pharmacogenomics J

View full text Add to dashboard Cite

show abstract

“…Although the variant al-leles in position 2677 and 3435 of ABCB1 have been found to modify intestinal MDR1 expression, 15,19 the absence of such an influence in liver might be accounted for by the lack of intraindividual correlation between hepatic and intestinal MDR1 protein levels. 38 Furthermore, because of the low hepatic MDR1 content compared with human small intestine, 38 a genetic effect on protein expression might be mitigated by confounding factors such as underlying disease, drug treatment, or by our semiquantitative approach.…”

Section: Discussionmentioning

confidence: 99%

Interindividual variability of canalicular ATP-binding-cassette (ABC)–transporter expression in human liver

et al. 2006

View full text Add to dashboard Cite

Interindividual variability in hepatic canalicular transporter expression might predispose to the development of hepatic disorders such as acquired forms of intrahepatic cholestasis. We therefore investigated expression patterns of bile salt export pump (BSEP, ABCB11), multidrug resistance protein 3 (MDR3, ABCB4 ), multidrug resistance associated protein 2 (MRP2, ABCC2 ) and multidrug resistance protein 1 (MDR1, ABCB1) in healthy liver tissue of a white population. Protein expression levels were correlated with specific single nucleotide polymorphisms (SNPs) in the corresponding transporter genes. Hepatic protein expression levels from 110 individuals undergoing liver resection were assessed by Western blot analysis of liver plasma membranes enriched in canalicular marker enzymes. Each individual was genotyped for the following synonymous (s) and nonsynonymous (ns) SNPs: ABCB11: (ns:1457T>C and 2155A>G), ABCB4: (ns:3826A>G) and ABCC2 (ns:1286G>A,3600T>A and 4581G>A) and ABCB1 (ns: 2677G>T/A and s:3435C>T). Transporter expression followed unimodal distribution. However, of all tested individuals 30% exhibited a high expression and 32% a low or very low expression phenotype for at least one of the four investigated transport proteins. Transporter expression levels did not correlate with age, sex, underlying liver disease, or presurgery medication. However, low BSEP expression was associated with the 1457C-allele in ABCB11 (P ‫؍‬ .167) and high MRP2 expression was significantly correlated with the 3600A and 4581A ABCC2 variants (P ‫؍‬ .006). In conclusion, the results demonstrate a considerable interindividual variability of canalicular transporter expression in normal liver. Furthermore, data suggest a polymorphic transporter expression pattern, which might constitute a risk factor for the development of acquired forms of cholestatic liver diseases. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/ index.html). (HEPATOLOGY 2006;44:62-74.)

show abstract

“…Indeed, the calculated intrinsic clearance of 1,25(OH) 2 D 3 by UGT1A4, compares reasonably well (21-51%) with that of the sapogenins, androstanediol and pregnanediol, compounds that are considered excellent UGT1A4 substrates [24]. 2 D 3 has been investigated in rats using quantitative whole-body autoradiography [Kissmeyer]. After dosing (ca; 12 μg), total radioactivity in liver at 8 hr was 1.5-fold higher than that in blood (121 vs 79 ng/g tissue) although the composition of 1,25 (OH) 2 D 3 in each tissue was unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Much of this variability results from differences in CYP3A4 protein content, which can vary more than 8-fold even in mucosal epithelium obtained from healthy volunteers [1,2]. Although the source of that variability is probably multi-factorial, some studies have documented dynamic changes in CYP3A4 transcription that can occur following activation of the vitamin D receptor (VDR) by its natural ligand, 1α,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) [3,4,5,6].…”

Section: Introductionmentioning

confidence: 99%

Identification of human UDP-glucuronosyltransferases catalyzing hepatic 1α,25-dihydroxyvitamin D3 conjugation

Hashizume¹,

Xu²,

Mohutsky³

et al. 2008

Biochemical Pharmacology

View full text Add to dashboard Cite

The biological effects of 1α,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) are terminated primarily by P450-dependent hydroxylation reactions. However, the hormone is also conjugated in the liver and a metabolite, presumably a glucuronide, undergoes enterohepatic cycling. In this study, the identity of human enzymes capable of catalyzing the 1,25(OH) 2 D 3 glucuronidation reaction was investigated in order to better understand environmental and endogenous factors affecting the disposition and biological effects of vitamin D 3 . Among twelve different UGT isozymes tested, only UGT1A4 ≫ 2B4 and 2B7 supported the reaction. Two different 1,25(OH) 2 D 3 monoglucuronide metabolites were generated by recombinant UGT1A4 and human liver microsomes. The most abundant product was identified by mass spectral and NMR analyses as the 25-O-glucuronide isomer. The formation of 25-O-glucuronide by UGT1A4 Supersomes and human liver microsomes followed simple hyperbolic kinetics, yielding respective K m and V max values of 7.3 and 11.2 μM, and 33.7 ± 1.4 and 32.9 ± 1.9 pmol/min/mg protein. The calculated intrinsic 25-O-glucuronide M1 formation clearance for UGT1A4 was 14-fold higher than the next best isozyme, UGT2B7. There was only limited (4-fold) inter-liver variability in the 25-O-glucuronidation rate, but it was highly correlated with the relative rate of formation of the second, minor metabolite. In addition, formation of both metabolites was inhibited > 80% by the selective UGT1A4 inhibitor, hecogenin. If enterohepatic recycling of 1,25(OH) 2 D 3 represents a significant component of intestinal and systemic 1,25(OH) 2 D 3 disposition, formation of monoglucuronides by hepatic UGT1A4 constitutes an important initial step.

show abstract

Cytochrome P450 3A4 and P‐glycoprotein Expression in Human Small Intestinal Enterocytes and Hepatocytes: A Comparative Analysis in Paired Tissue Specimens

Cited by 245 publications

References 47 publications

Effects of diltiazem on pharmacokinetics of tacrolimus in relation to CYP3A5 genotype status in renal recipients: from retrospective to prospective

Effects of diltiazem on pharmacokinetics of tacrolimus in relation to CYP3A5 genotype status in renal recipients: from retrospective to prospective

Interindividual variability of canalicular ATP-binding-cassette (ABC)–transporter expression in human liver

Identification of human UDP-glucuronosyltransferases catalyzing hepatic 1α,25-dihydroxyvitamin D3 conjugation

Contact Info

Product

Resources

About